Title

Author

Date of Award

1990

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmacology

First Committee Member

Lincoln T. Potter, Committee Chair

Abstract

This dissertation consists of four projects in which I investigated the rationale for cholinergic replacement therapy in Alzheimer's disease.There is a well established cholinergic deficit in the cortex and hippocampus of patients with Alzheimer's disease (AD). These data have lead to attempts to treat AD by restoring cholinergic input with drugs such as tetrahydroaminoacridine (THA), or with muscarinic agonists.In the first project I measured the actions of THA on esterases and on muscarinic receptors under physiological conditions. I found that at concentrations above 1 $\mu$M, THA interacts with M$\sb1$ and M$\sb2$ muscarinic receptors at primary and allosteric sites. However, clinically effective concentrations range from 0.03-0.3 $\mu$M and in this concentration range I found THA to be an effective esterase inhibitor. Thus THA probably acts clinically as an acetylcholinesterase inhibitor.Two other projects concerned the status of the first steps in the transduction mechanism for postsynaptic muscarinic receptors in AD and long after experimental cholinergic denervation. I performed competition experiments between 1 nM 3H-pirenzepine (which is believed to label m1 muscarinic receptors selectively) and oxotremorine-M to assess the effects of aging, AD and longterm experimental denervation of the hippocampus on m1 receptor-G protein interactions. Using guanine nucleotide-sensitive agonist binding as a measure of such interactions, I found no change in m1 receptor-G protein coupling in cortex from patients with AD or several other dementias, or in rat hippocampi one year after fimbria/fornix lesions. These m1 receptor-G protein interactions were also not affected by aging in rats, or in the human cases. I also found normal muscarinic agonist-stimulated phosphoinosotide hydrolysis in rat hippocampi 1.3-1.5 years after fimbria/fornix lesions. These data indicate that the first few steps in the transduction mechanisms for postsynaptic muscarinic receptors remain intact even when there is chronic receptor disuse. In a fourth project I found that dramatic changes in dietary lipids do not lead to alterations in m1 receptor-G protein coupling in rats. I concluded from these studies that cholinergic replacement therapy is a rational approach to ameliorating the symptoms of AD, in the absence of better information on its etiology.